Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 47

Prolonged neuronal activity during seizure discharges may also have the effect of increasing CO2 or increasing the by-products of anaerobic metabolism, and produce extra-cellular acidosis or intracellular acidosis associated with extracellular alkalinosis (Chesler and Kaila, 1992). Glial cells may also contribute to acidification of the extracellular space in response to increases in the extracellular potassium concentration (Chesler and Kraig, 1987). In the hippocampal slice in vitro, acidification of the extracellular space to pH 6.7 terminated seizure-like burst firing facilitated by low-magnesium in the artificial CSF. The attenuation of epileptiform activity began within minutes of lowering pH (Velisek et al., 1994; Velisek, 1998). The mechanisms of action – at least in part – included decreased NMDA receptor function and loss of synaptic long-term potentiation (LTP). A milder reduction of pH to 7.1 also produced milder synaptic impairment with continued loss of LTP (Velisek, 1998). Inhibition of carbonic anhydrase, which alters extracellular pH, has some anticonvulsant benefit. In humans, the carbonic anhydrase inhibitor acetozolamide has a mild anticonvulsant effect (Thiry et al., 2007). Knockout mice deficient in carbonic anhydrase are severely acidotic and are resistant to seizures produced by flurothyl gas compared to wild-type mice (Velisek et al., 1993). Intracellular acidification may also contribute to termination of seizure discharges. Spontaneous interictal spiking following focal application of bicuculline in the piriform cortex in an in vitro whole brain preparation was associated with periodic abrupt alkanization of the extracellular space followed by a slow return to baseline pH (de Curtis et al., 1998). These observations were interpreted as evidence of intracellular acidification. Application of ammonium chloride in the perfusing medium to prevent intracellular acidification increased neuronal excitability and resulted in after-discharges following each spike, and in seizure-like discharges. The investigators hypothesized that the intracellular acidification reduced excitability by reducing gap-junction function. Application of octanol, a nonspecific gap junction blocker, abolished spontaneous interictal spiking (de Curtis et al., 1998).